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Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors

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资源类型：
Pubmed体系：
作者：
Wang Feng[1] * ; Liu Donglan[2,3] * ; Gao Dingding[1] ; Yuan Jinwei[2] ; Zhao Jingxian[2] ; Yuan Shuai[6] ; Cen Yixin[1] ; Lin Guo-Qiang[1] ; Zhao Jincun[2,3,4,5] ; Tian Ping[1] ;
机构： [1]The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. [2]State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China [3]Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong 510320, China. [4]Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China [5]Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China. [6]Health and Quarantine Laboratory, Guangzhou Customs District Technology Center, Guangzhou 510700, China.
出处：
DOI： 10.1016/j.ijbiomac.2024.130377
ISSN：

关键词： SARS-CoV-2 3CLpro Covalent inhibitors Catechol derivatives Antiviral activities

摘要：
The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a threat to public health, and extensive research by scientists worldwide has also prompted the development of antiviral therapies. The 3C-like protease (3CLpro) is critical for SARS-CoV-2 replication and acts as an effective target for drug development. To date, numerous of natural products have been reported to exhibit inhibitory effects on 3CLpro, which encourages us to identify other novel inhibitors and elucidate their mechanism of action. In this study, we first screened an in-house compound library of 101 natural products using FRET assay, and found that oleuropein showed good inhibitory activity against SARS CoV-2 3CLpro with an IC50 value of 4.18 μM. Further studies revealed that the catechol core is essential for activity and can covalently bind to SARS-CoV-2 3CLpro. Among other 45 catechol derivatives, wedelolactone, capsazepine and brazilin showed better SARS-CoV-2 3CLpro inhibitory activities with IC50 values of 1.35 μM, 1.95 μM and 1.18 μM, respectively. These catechol derivatives were verified to be irreversible covalent inhibitors by time-dependent experiments, enzymatic kinetic studies, dilution and dialysis assays. It also exhibited good selectivity towards different cysteine proteases (SARS-CoV-2 PLpro, cathepsin B and cathepsin L). Subsequently, the binding affinity between brazilin and SARS-CoV-2 3CLpro was determined by SPR assay with KD value of 0.80 μM. Molecular dynamic (MD) simulations study showed the binding mode of brazilin in the target protein. In particular, brazilin displayed good anti-SARS-CoV-2 activity in A549-hACE2-TMPRSS2 cells with EC50 values of 7.85 ± 0.20 μM and 5.24 ± 0.21 μM for full time and post-infection treatments, respectively. This study provides a promising lead compound for the development of novel anti-SARS-CoV-2 drugs.Copyright © 2024 Elsevier B.V. All rights reserved.

基金：
We gratefully acknowledge the National Key R&D Program of China (2022YFF1202600), the National Natural Science Foundation of China (Nos: 22371188, 22071155, 82025001, 81971500) the Open Project of Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs (SMECD2022003), the Shanghai Municipal Education Commission (No.: 2019-01-07-00-10-E00072), the Science and Technology Commission of Shanghai Municipality (20400750300), the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202004), the Shanghai Municipal Health Commission/Shanghai Municipal Administration of Traditional Chinese Medicine [ZY(2021-2023)-0501], the Organizational Key R&D Program of SHUTCM (2023YZZ01), the Outstanding Doctoral Student Cultivating Projects of SHUTCM (2022-2-071), and the Guangdong Basic and Applied Research Projects (2021B1212030016).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类 | 1 区 化学
小类 | 1 区 应用化学 1 区 高分子科学 2 区 生化与分子生物学
最新[2025]版：
大类 | 2 区 生物学
小类 | 2 区 生化与分子生物学 2 区 应用化学 2 区 高分子科学
第一作者：
第一作者机构： [1]The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
共同第一作者：
通讯作者：
通讯机构： [2]State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China [3]Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong 510320, China. [4]Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China [5]Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
推荐引用方式(GB/T 7714)：
Wang Feng,Liu Donglan,Gao Dingding,et al.Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors[J].International Journal Of Biological Macromolecules.2024,264(Pt 1):130377.doi:10.1016/j.ijbiomac.2024.130377.
APA：
Wang Feng,Liu Donglan,Gao Dingding,Yuan Jinwei,Zhao Jingxian...&Tian Ping.(2024).Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors.International Journal Of Biological Macromolecules,264,(Pt 1)
MLA：
Wang Feng,et al."Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors".International Journal Of Biological Macromolecules 264..Pt 1(2024):130377

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